The compound of the present invention is known in prior art literature as early as the nineteen seventies in connection with their utility in synthesis of steroidal alkaloids and saponines [S. V. Kessar and A. L. Rampal, Chem Ind., 1957 (1963); Tetrahedron Letters, 4319 (1966). These compounds were later isolated from the resin (gum guggul) obtained from Commiphora mukul which is an important drug in the Ayurvedic system for arthritis and inflammation.
There is also reference regarding its anti-obesity activity in Charak Sanghita [G. V. Satyavati in Economic and Medicinal Plant Research, Vol. 5, Plants and Traditional Medicine pp 47 (1991), Academic Press]. After extensive research work on gum-guggul through extractive fractionation followed by bio-evaluation at Central Drug Research Institute, Lucknow jointly with Malti-Chem Research Centre, Baroda, a toxicologically safe extract was standardized for hypolipidemic activity.
The product is being marketed as ‘Guglip’ by CIPLA Ltd., Bombay. It was simultaneously established in the study that hypolipidemic activity was due to presence of compounds of formula Ia and Ib above to the extent of 4-5% in the product and hence the name guggulsterone was coined to the product I.
The results of this pioneering work provoked considerable efforts among industries and academia world-over in Guglip and as a result several additional activities were established in the preparation such as prevention of sebum secretion [U.S. Pat. No. 5,6980, 948], anti-inflammatory by Bombardelli et al [U.S. Pat. No. 5,273,747] and use in benign prostate hypertrophy and acne. Bessett et al [U.S. Pat. No. 4,847,071 and 4, 847, 069] and Piazza et al [U.S. Pat. No. 5,521,223] disclosed photo-protective and anti wrinkle actions. Guggulsterone content in gugulipid is highest to the extent of 4-5% and therefore many of the activities of gugulipid have been implicated because of guggulsterone.
The hypolipidermic activity has already been established. In pursuance of further efforts in synthesis of guggulipid and its constituents, the process of guggulsterone synthesis has been further improved upon.
Two methods of guggulsterone synthesis are known. The first method is as follows:
5,17 (20)-pregnadiene-3,16-diol (Scheme I, compound V) is the key intermediate in the synthesis [WR Benn and RM Dodson, J. Org. Chem. 29, 1142 (1964)]. The reduction of α, β-unsaturated carbony] function of 16-DPA with lithiumaluminumphydride (LAH) yields 5, 16-pregnadiene 3, 20-diol (III) which on catalyzed allylic rearrangement produces the key intermediate IV. The oxidation of IV yields guggulsterone.
However, the process has many drawbacks. During the process of reduction, a by-product through 1,4-hydride addition is always inevitable (to the extent of 40%) and hence a chromatographic separation is required. The slight impurity of this product will contaminate the final product with progesterone after oxidation on the other hand, use of pyrrophoric and inflammable reagents like LAH and solvent ether at industrial scale is also a cause of reluctance for industrial production [W. R. Benn, J. Org. Chem. 28, 3557 (196)].
The alternate process is as follows:
The unsaturated carbonyl function of 16-DPA is converted to 16,17-epozy carbonyl followed by Kishner reduction-elimination under Huang-Minlon condition yields the key intermediate (Scheme 2).
However, this procedure is also not suitable for large-scale preparation because of simultaneous formation of pyrazone, a by-product in appreciable high yields. The epoxidation with hydrogen peroxide is not reproducible instead a Michael addition product is obtained as a by-product in reported conditions. Also because of the supply of hydrogen peroxide of variable strength, it is difficult to fix the reaction parameters.
